Hypofractionated external beam radiotherapy has actually been used clinically for a number of years, particularly in the UK.^{21}^{–}^{23} While these treatments were generally well tolerated, overall efficacy is difficult to assess, given that these trials were carried out largely in the pre-PSA era. A number of more contemporary hypofractionation trials, either published or currently in progress, are shown in . The most straightforward and intuitive way of estimating the predicted effectiveness and toxicities of these various approaches is to use the linear quadratic modeling to equate the various hypofractionation practices to the normalized equivalent dose (NED) if delivered in 2 Gy fractions. These are shown in for assumed α/β of 1.5 and 3 for prostate cancer and late responding normal tissue, respectively. It is first of all apparent that, even for these only modestly hypofractionated schedules, normalized doses range between about 4 and 8 % higher for tumor than for normal tissue, illustrating the potential for therapeutic gain even with relatively modest hypofractionation should prostate cancer in fact have a lower α/β ratio than normal tissue.

| **Table 1**Hypofractionation Trials: Schedules and Equivalent Total Doses in 2-Gy Fractions |

Of those above trials that are contemporary, are completed and are reported, only the Princess Margaret^{29}, Cleveland Clinic^{20}, Manchester^{24}, NCI-Canada^{31} and Chiba carbon ion^{26} trials have sufficient numbers of patients and sufficient albeit still relatively short follow-up to enable preliminary estimates of biochemical control and toxicity. Of these five, only the Princess Margaret, Cleveland Clinic and Chiba carbon ion trials deliver equivalent doses sufficiently large enough (assuming α/β = 1.5) to currently be considered adequately dose escalated. Additionally, only these three trials included sufficient patient numbers and follow-up to adequately estimate late toxicity.

Reported toxicity in these three trials was quite acceptable, with the actuarial RTOG Grade ≥ 2 late rectal and genitourinary toxicity rates being only 2% and 2%, 4.5% and 5.3%, and 1% and 1% for the Princess Margaret, Cleveland Clinic and Chiba trials, respectively. Efficacy also has appeared to be satisfactory. An analysis of biochemical control in the Cleveland clinic trial yielded a 5 years overall rate of 82%, equivalent to or better than previously attained with the institutional standard of 78 Gy in 2 Gy fractions.^{20} The Chiba trial found an overall biochemical control rate of 83% at 5 years.

The Manchester study^{24} used a schedule delivering lower equivalent doses and accordingly reported low late toxicities and relatively poor biochemical control rates, consistent with results expected for a “conventional” doses of only 66 Gy in 2 Gy fractions. Similarly, the NCI-Canada trial employed a schedule equivalent to only about 62 Gy in 2 Gy fractions.^{31} Biochemical control rates and toxicities were also correspondingly low. In spite of the low equivalent doses these two trials delivered, comparisons of their reported outcomes can enable a useful testing of hypofractionation modeling. The Princess Margaret and Cleveland Clinic studies, with their higher delivered equivalent doses, are valuable for such testing as well.

A graphical depiction of biochemical control rates versus equivalent dose from these four studies (for intermediate risk prostate cancer, when specifically reported) is presented in . Represented are 3–5 year actuarial bDFS rates using the ASTRO definition, the only definition uniformly available in these reports. The solid line dose response curve for radiation delivered in 2 Gy fractions is adapted from Fowler *et al*
^{18} and is based upon 5 year biochemical control data for intermediate risk patients from 5 conventionally fractionated prostate cancer trials. Biochemical control points from the hypofractionation trials are plotted relative to their equivalent dose for three assumed α/β ratios of 1.5, 3 and 10. The ratio of 1.5 clearly produces the closest fit to the curve. While many unaccounted for variables render this a non-rigorous and strictly post hoc comparison, the degree of outcomes agreement between hypofractionated and conventional regimens when an α/β of 1.5 is chosen intriguingly suggests that prostate cancer response is indeed characterized by a low α/β ratio.

A more formalized analysis by Bentzen and Ritter^{35} of one of these trials, the NCI-Canada study^{31}, again but more rigorously yields a quite low α/β ratio estimate for prostate of 1.12 Gy with 95% confidence interval (−3.3, 5.6) Gy.

The final non-randomized study listed in is a multi-institutional trial (University of Wisconsin, M.D. Anderson-Orlando, Wayne State University, Medical college of Wisconsin and JT Vucurevich Cancer Inst., Rapid City) and is a phase I/II study^{30} that escalates dose per fraction in three steps, with late rectal bleeding the escalation-limiting factor. The design results in predicted late effects expected to remain relatively constant (at a level consistent with about 76 Gy delivered in 2 Gy fractions) even as fraction size escalates. The trial design also includes a nested fractions-per-week escalation/de-escalation to monitor for and prevent unacceptable acute toxicities that might result from too extreme a shortening of treatment duration. Overly severe acute toxicities not only create intratreatment morbidity, but might also lead to so-called consequential late injuries in adjacent organs such as rectum or bladder.^{18}

Preliminary results from this phase I/II trial^{30} have indicated acceptably low rates of GI and GU toxicity (2 years grade 2 GI and GU toxicity rates of 8.8 and 3%, respectively, even after five-day-per-week treatment, and, also, preliminary biochemical control rates that are high and in the expected range. The trial is nearing completion with 258 of a target 300 patients accrued. When mature, its three increasingly hypofractionated schedules will be evaluable in terms of their suitability for future trials and, in addition, collected and centrally analyzed dose-volume data together with the trial’s three significantly different doses per fraction should permit solid estimates to be made of α/β ratios both for prostate cancer as well as for adjacent organs at risk.

Thus, the outcomes of several hypofractionation trials support the hypothesis that the α/β ratio for prostate cancer is low and that further investigation via prospective, preferably randomized clinical trials is fully warranted. As is also evident from , several such randomized trials that deliver suitably high effective doses have either recently completed accrual or are currently underway. Thus the prospects for a comprehensive evaluation of this potentially clinically advantageous, cost effective and convenient treatment approach appear excellent. Ideally, these or future trials will also adequately collect delivered rather than planned dose-volume information, enabling the most accurate analysis of the fractionation response of prostate cancer and normal tissue. The methodology to do so has become available and its use should be encouraged.